This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project seeks to develop and validate a spatially-modulated, scatter-based imaging system with the long term goal of assessing, intra-operatively, surgical excision margin status for involvement of cancer. In the case of breast cancer, such a system would have a profound impact on the 32-63% of women nationwide [1,2] who currently require separate re-excision procedures following breast-conserving surgery where tumor is subsequently found to involve one or more of the resection margins. If residual tumor can be identified in the surgical cavity at the time of the original excision, then more tissue can be removed immediately to clear the margin rather than during a later, separate surgical procedure. Two new discoveries in tissue optics,related to quantitative scatter-based imaging, serve as the basis for this proposal. The first discovery is the unique and currently unexploited finding, at Dartmouth, that breast carcinomas and their associated stroma have high phase contrast, and hence high scattering, when compared to surrounding adipose and benign fibroglandular tissue [3]. The second discovery is the development, at UC Irvine, of a portable, spatiallymodulated imaging system with light transport modeling to determine optical absorption and scattering that is ideally suited for quantitative scatter-based imaging in bulk tissue samples [4,5]. This proposal tests the hypothesis that tumor-associated stroma has a distinctly different scattering signature which can be used diagnostically to detect areas of tumor involvement during surgery. The hypothesis will be tested in a series of specific aims that progress from system development and validation to a prospective clinical implementation in the future. The specific R21 aims are: Year 1: Aim 1: Develop a portable, spatially-modulated imaging system for quantitative, scatter-based imaging in bulk tissue samples. Aim 2: Demonstrate that the imaging system can differentially quantify scatter in the benign tissue types represented in reduction mammoplasty specimens (adipose tissue, glandular epithelium, support stroma) as validated by the gold standard clinical pathologic diagnosis Year 2: Aim 3: Demonstrate that scatter imaging can differentiate tumor versus non-tumor associated stroma in excised breast cancers (lumpectomies) as validated by the gold standard clinical pathologic diagnosis Aim 4: Determine whether the sensitivity, specificity and positive predictive value of the imaging system, and its logistical feasibility, warrant its use in the intra-operative evaluation of margin involvement by cancer in breast-conserving lumpectomies.